Biological importance of the two Toll-like receptors, TLR2 and TLR4, in macrophage response to infection with<i>Candida albicans</i>

Blasi, Elisabetta; Mucci, Anna; Neglia, Rachele Giovanna; Pezzini, Francesco; Colombari, Bruna; Radzioch, Danuta; Cossarizza, Andrea; Lugli, Enrico; Volpini, Gianfranco; Giudice, Giuseppe Del; Peppoloni, Samuele

doi:10.1016/j.femsim.2004.12.005

Cited by 69 publications

(54 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similarly to our results, TLR2-deficient macrophages exhibited an increased ability to contain another fungal pathogen, C. albicans, but this fact was not associated with different patterns of cytokine production (37). The in vivo infection of TLR2-deficient mice resulted in decreased fungal burdens in all postinfection periods assayed.…”

Section: Discussionsupporting

confidence: 84%

TLR2 Is a Negative Regulator of Th17 Cells and Tissue Pathology in a Pulmonary Model of Fungal Infection

Loures

Pina²,

Felonato³

et al. 2009

The Journal of Immunology

143

133

View full text Add to dashboard Cite

To study the role of TLR2 in a experimental model of chronic pulmonary infection, TLR2-deficient and wild-type mice were intratracheally infected with Paracoccidioides brasiliensis, a primary fungal pathogen. Compared with control, TLR2−/− mice developed a less severe pulmonary infection and decreased NO synthesis. Equivalent results were detected with in vitro-infected macrophages. Unexpectedly, despite the differences in fungal loads both mouse strains showed equivalent survival times and severe pulmonary inflammatory reactions. Studies on lung-infiltrating leukocytes of TLR2−/− mice demonstrated an increased presence of polymorphonuclear neutrophils that control fungal loads but were associated with diminished numbers of activated CD4+ and CD8+ T lymphocytes. TLR2 deficiency leads to minor differences in the levels of pulmonary type 1 and type 2 cytokines, but results in increased production of KC, a CXC chemokine involved in neutrophils chemotaxis, as well as TGF-β, IL-6, IL-23, and IL-17 skewing T cell immunity to a Th17 pattern. In addition, the preferential Th17 immunity of TLR2−/− mice was associated with impaired expansion of regulatory CD4+CD25+FoxP3+ T cells. This is the first study to show that TLR2 activation controls innate and adaptive immunity to P. brasiliensis infection. TLR2 deficiency results in increased Th17 immunity associated with diminished expansion of regulatory T cells and increased lung pathology due to unrestrained inflammatory reactions.

show abstract

Section: Discussionsupporting

confidence: 84%

TLR2 Is a Negative Regulator of Th17 Cells and Tissue Pathology in a Pulmonary Model of Fungal Infection

Loures

Pina²,

Felonato³

et al. 2009

The Journal of Immunology

143

133

View full text Add to dashboard Cite

show abstract

“…However, no increase in the TLR4 message was observed in this study (11). Although a role for TLR2 in activation of DC during E. cuniculi was not observed in our study, it is possible that TLR2 may be involved in activation of other antigen-presenting cells, like macrophages, as reported in previous studies (3). Alternatively, it is very likely that TLRs involved in the responses to microsporidian infections in human and mouse macrophages or DC are different.…”

Section: Discussioncontrasting

confidence: 56%

“…DC are known to initiate an immune response through recognition of pathogen-associated molecular patterns (PAMPS) by Toll-like receptors. Microsporidia consist of a chitinous spore wall that contains O-linked glycans similar in structure to those found in the cell wall of Candida albicans (38), which has been shown to signal through TLR2 and -4 (3,14). Additionally, microsporidia contain glycosylphosphatidylinositol (GPI) anchors analogous to those found in Trypanosome cruzi, Plasmodium falciparum, and Toxoplasma gondii, all of which activate TLR2 and/or TLR4 (4,8,22,28).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Optimal CD8 T-Cell Response againstEncephalitozoon cuniculiIs Mediated by Toll-Like Receptor 4 Upregulation by Dendritic Cells

2010

View full text Add to dashboard Cite

CD8؉ T-cell immunity has been shown to play an important role in the protective immune response against Encephalitozoon cuniculi. Although earlier studies suggest that dendritic cells (DC) are important for the induction of this response, the factors responsible for initiation of the dendritic cell response against this pathogen have not been evaluated. In the current study, we demonstrate that E. cuniculi infection causes strong Toll-like receptor 4 (TLR4)-dependent dendritic cell activation and a blockade of this molecule reduces the ability of DC to prime an antigen-specific CD8 ؉ T-cell response. Pretreatment of DC with anti-TLR4 antibody causes a defect in both in vitro and in vivo CD8 ؉ T-cell priming. These findings, for the first time, emphasize the contribution of TLR4 in the induction of CD8 ؉ T-cell immunity against E. cuniculi infection.Microsporidia are small obligate intracellular parasites that, until recently, were thought to be protozoans; however, evidence now suggests that they are related to fungi (15,17). Microsporidia can infect a vast number of species of vertebrates and invertebrates; of the 150 genera of microsporidia, however, only 7 have been found to infect humans (13). Severe infections have been reported predominantly for immunocompromised patients, such as patients with HIV and organ transplant recipients (2,7,23,37). Acute infections have also been reported in travelers and the elderly (26, 27), and there is evidence of colonization of healthy, nonsymptomatic patients (34).Due to the prevalence of opportunistic microsporidian infections associated with the HIV-AIDS pandemic, recent research has focused on the host's immune response to these pathogens. Early animal studies showed that cellular immunity was necessary to protect SCID mice from a lethal Encephalitozoon cuniculi challenge. Moreover, depletion of CD8 ϩ T cells caused mice to succumb to intraperitoneal (i.p.) E. cuniculi infection (21), and previous studies in our laboratory have shown that cytotoxic lymphocytes play a major role in protection against this effect (20,21).Recent reports from our laboratory have demonstrated that dendritic cells (DC) play an important role in the priming of the immune response against E. cuniculi (31, 32). T cells incubated with E. cuniculi-pulsed DC exhibited antigen-specific characteristics, specifically gamma interferon (IFN-␥) production, cytotoxicity, and proliferation (31, 32). In order to mount an immune response against a foreign pathogen, DC must first recognize the pathogen to initiate an appropriate response. One key method of recognition is through Toll-like receptors (TLRs), which were first discovered in Drosophila in response to infection with fungal pathogens (24). However, specific TLR molecules involved in DC activation during E. cuniculi infection have not been identified previously. We evaluated the upregulation of specific molecules involved in activation of the DC response after E. cuniculi infection. Different TLR molecules were tested, and TLR4 expression was found ...

show abstract

“…A bone marrow-derived macrophage cell line named T4Cr from TLR4-deficient C57BL/10ScNCr mice and a cell line named WTSn from wild-type C57BL/10ScSn mice (Table I) were established by expression of the viral genes, v-myc and v-raf (21,24). WTSn cells and T4Cr cells were rounder in culture than primary bone marrow macrophages, but the cell lines looked similar to each other (Fig.…”

Section: Creation and Characterization Of Tlr4-deficient And Wild-typmentioning

confidence: 99%

Abrupt Expression of TLR4 in TLR4-Deficient Macrophages Imposes a Selective Disadvantage: Genetic Evidence for TLR4-Dependent Responses to Endogenous, Nonmicrobial Stimuli

Cohn

Nathan²,

Radzioch

et al. 2006

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

TLR4 is crucial for macrophage responses to LPS. It is less clear whether TLR4 may also transduce signals from host factors, and if so, with what consequences. Immortalized bone marrow-derived macrophage cell lines, termed T4Cr and T4ko, were established from TLR4null strains, C57BL/10ScNCr and TLR4 knockout mice, respectively. Multiple transfections and selections were conducted to stably introduce TLR4 into these cell lines. Among 196 individual clones isolated, 48 expressed TLR4 on the cell surface but did not respond to LPS due to a deletion in the MyD88 gene. The remaining clones integrated TLR4 DNA into the genome but expressed neither detectable TLR4 mRNA nor TLR4 protein. To test the possibility that TLR4null cells lack modulating factors to protect against a harmful effect of TLR4, 15 stably transfected clones were generated in the presence of conditioned media from wild-type macrophages. Some of these cells expressed a small amount of TLR4 and regained responsiveness to LPS. Because no microbial ligands were available to the cell lines during their generation, signaling via endogenous ligands is likely to have occurred in TLR4-expressing, signal-competent macrophages and imposed a proliferative or other selective disadvantage. These studies support the existence of constitutive signaling via TLR4 during in vitro culture of macrophages without microbial products, and help account for the lack of reports of restoration of TLR4 expression in normally TLR4-expressing types of cells in vitro whose TLR4 genes are deleted or disrupted.

show abstract

Biological importance of the two Toll-like receptors, TLR2 and TLR4, in macrophage response to infection withCandida albicans

Cited by 69 publications

References 48 publications

TLR2 Is a Negative Regulator of Th17 Cells and Tissue Pathology in a Pulmonary Model of Fungal Infection

TLR2 Is a Negative Regulator of Th17 Cells and Tissue Pathology in a Pulmonary Model of Fungal Infection

Optimal CD8 T-Cell Response againstEncephalitozoon cuniculiIs Mediated by Toll-Like Receptor 4 Upregulation by Dendritic Cells

Abrupt Expression of TLR4 in TLR4-Deficient Macrophages Imposes a Selective Disadvantage: Genetic Evidence for TLR4-Dependent Responses to Endogenous, Nonmicrobial Stimuli

Contact Info

Product

Resources

About